Among Intensive Care Unit (ICU) survivors, subsequent cognitive and functional decline are the greatest threats to meaningful recovery. Six small cohorts indicate that an alarming 30% to 80% of the increasingly older millions of ICU survivors develop an acquired long-term cognitive impairment (LTCI) functionally equivalent to mild/moderate dementia that may last years. Additionally, major deficits in health-related quality of life (HRQL), functional status, and an "ICU accelerated" frailty are common, especially in the elderly. A leading and potentially modifiable risk factor for these devastating outcomes may be ICU delirium, which is a predictor of higher mortality, higher cost, and poor cognitive function at discharge. Additionally, heavy and prolonged exposure to potent psychoactive medications routinely administered in high doses to ventilated patients may have lasting yet preventable cognitive and functional effects. In this proposal, Aims 1 and 3 will determine whether delirium is an independent risk factor for the incidence, severity, and/or duration of LTCI (Aim 1) and impaired HRQL (Aim 3) in ICU survivors. Likewise, Aims 2 and 4 will determine whether degree of exposure to sedative and analgesic medications in ICU patients is an independent risk factor for the incidence, severity, and/or duration of LTCI (Aim 2) and impaired HRQL (Aim 4). The MIND- ICU study will be a prospective cohort study enrolling 800 mechanically ventilated medical and surgical patients from 3 diverse medical centers over a 39 month period with comprehensive follow-up testing at 3 and 12 months after hospital discharge. This study will quantify whether delirium and sedative/analgesic exposure are indeed risk factors for LTCI and HRQL, controlling for other covariates such as age, medical vs. surgical ICU admission, pre-existing cognitive impairment, sepsis, and apoE genotype. This will pave the way for development of preventive and/or treatment strategies to reduce long-term cognitive impairment and improve the functional recovery of older and younger ICU patients for decades to come. LAY SUMMARY: Major threats to recovery for ICU survivors are acquired cognitive and functional decline that can last years, especially in older pateints. To pave the way for future preventive and interventional strategies, the MIND-ICU cohort will determine to what degree delirium and potent sedatives and analgesics are risk factors for long-term cognitive impairment and functional decline following critical illness.